Large numbers of individuals in the United States and elsewhere suffer from constant debilitating pain. These individuals include victims of terminal diseases and chronic diseases such as osteoarthritis.
Ongoing attempts have been made to provide a more potent analgesic which can be self-administered and which is nonaddicting. While certain well-known and effective analgesics, such as morphine and here in, are in fact available, they lack useful oral activity and because of their potential for abuse, their use has been restricted, and the most effective forms have been denied even to terminal patients because of the vulnerability of supplies to theft.
Research to provide an effective but nonaddicting analgesic has understandably centered around structural analogs of the naturally occurring codeine and morphine compounds. A number of N-sec-alkyl analogs of normorphine have been prepared and are described in U.S. Pat. Nos. 4,269,843 and 4,218,454 to DeGraw et al., the disclosures of which are hereby incorporated by reference. A number of these N-e-methylhydrocarbyl derivatives were reported to have biological activity, and a number of them were capable of resolution into the two diastereomeric forms generated with respect to the chiral center at the .alpha.-carbon. Among those compounds which were thought at first to be incapable of resolution were N-.alpha.-methylcyclopropylmethyl normorphine (i.e., N-(1'cyclopropyl-ethyl)-normorphine) and the corresponding norcodeine compound. Resolution of these compounds was ultimately achieved as described in commonly assigned U.S. Pat. No. 4,749,706, inventors Lawson et al., also incorporated by reference herein. These compounds were found to have high analgesic activity and may be readily synthesized, i.e., using the methodology set forth in the '706 patent.
Nevertheless, there remains a need in the art for pharmaceutical compositions which have very high analgesic activity when administered either orally or parenterally, and which have a low potential for abuse. The present invention relates to such compositions, and more specifically relates to pharmaceutical compositions containing certain species of the diester intermediates described generically in U.S. Pat. No. 4,749,706 at columns 3-4, bridging paragraph, and to methods of administering those compounds and compositions so as to achieve analgesia. The present invention also relates to pharmaceutical compositions containing other, related normorphine and norcodeine analogs, and to methods of using those compounds as analgesic agents.